A total of 82 half-hour episodes were produced, including one hour-long Holiday special and four feature-length TV movies, bringing the total number of episodes to 86, in the form of 160 segments. The episode "Billy and Mandy Moon the Moon" was a part of Cartoon Network’s "Invaded" event, which included other shows such Foster's Home for Imaginary Friends, My Gym Partner's a Monkey, and Camp Lazlo, with The Grim Adventures of Billy & Mandy being the final show to air.

A scene of Endsville two weeks into the future shows a dystopian world ruled by the "Lord of Horror", who wields the all-powerful artifact known as "Horror's Hand". At the same time, two robotic replicas of Billy and Mandy are sent into the past, to stop the real Billy and Mandy from interfering with the current events.

In the present, Grim goes to reap General Skarr, who accidentally got a big wound in his torso. Due to Billy and Mandy's meddling, Skarr escapes, and they make a big mess in the city. Following his failure to be an effective Reaper, Grim is taken to the Underworld Court, presided by Judge Roy Spleen, where he is sued for misuse of his powers by his nemesis, the Boogeyman. Grim is found guilty, is stripped of his rank and magical scythe, and he, Billy, Mandy, and Irwin are sentenced to be exiled. Boogey volunteers to carry on the sentence by taking the prisoners aboard his ship, and dropping them off in a river of fire; he plans to do this while he sails to obtain Horror's Hand, an object capable of transforming him into the scariest, strongest and most powerful being in existence.

The group of Billy, Mandy, Irwin, and the powerless Grim, escapes from Boogey's ship when Billy distracts Boogey and his crew with the song "Scary-o", and set themselves to reach Horror's Hand before Boogey does. They eventually meet Horror, the guardian of the Hand, at the same time Boogey and his crew arrive. To decide who will have the honor to battle Horror for his Hand, the heroes and Boogey participate in a challenging obstacle course, which the heroes win against all odds. After dispatching Horror with ease, Billy, Mandy, and Irwin reach for the Hand, but it defends itself by making their worst nightmares come to life. Boogey gets hold of Horror's Hand, but he turns out to be the least scariest creature ever, seriously injuring himself, and being abandoned by his own crew.

Grim recovers Horror's Hand, and at the same time his sentence is revoked, becoming the Reaper once again. The future Billy arrives, telling them Horror's Hand should not fall in the wrong hands, specifically Mandy's as he indirectly reveals that she was the one who used Horror's Hand to rule the world. When they return home, Grim seals Horror's Hand in his bottomless trunk, and the future Billy returns to his own time. The future Billy realizes the situation in his time did not improve, and it is Fred Fredburger who obtained Horror's Hand to rule the world.

On a rainy day, giant spiders appear in Billy and Mandy's school and start kidnapping the children one by one. Grim presumes this is somehow related to his past, but does not figure it out until he receives a message saying that Velma, the Spider Queen, an old good friend from high school, is responsible for it. Meanwhile, Billy meets with Jeff the Spider, who informs him that he is precisely marrying Velma. After trying to recover a talking carton of chocolate milk from Jeff, Billy and Jeff get into a fight, and Jeff looks angrier than ever before.

Upon meeting in the school's football field, Velma tells Grim that she has finally come to devour his skull and absorb his magical and supernatural powers, since one hundred thousand years ago, Grim had cheated and robbed her from the possibility of becoming the Reaper in a scare election. Converting the school into her own palace, and with help from the Dark Elves, Velma captures Mandy, Mindy, and Grim, and proceeds to devour the latter's skull. When Velma cracks open Grim's skull, his thoughts start coming out in the form of light blue light, and she is able to see his past memories.

Grim's skull is connected to a projection screen, and the story on how he became the Reaper is shown. It is revealed that an election was held in the Underworld's high school to choose the Reaper, in which students had to vote on the scariest participant. Velma was the scariest contestant and she was getting most of the votes over the pathetic Grim and the Boogeyman. Boogey decided to tamper with the ballots, and Grim in turn decided to help Velma by filling the ballot with votes for her, but she got the impression that Grim was the cheater and ran away. In a fit of anger for what Boogey had caused, Grim used the prototype scythe in a spectacular fashion to scare Boogey off. The people that had not yet cast their vote voted for Grim, who became the new Reaper. While the story is being told, Mandy and Mindy form a temporary alliance to fight the spiders, and also Billy conquers his arachnophobia, and fights the spider-cow centaur-like extraterrestrial from the milk carton.

Velma realizes she was wrong, with respect to Grim, and she apologizes for the whole vengeful ordeal. After the wedding ceremony, Billy suddenly realizes Velma is a spider, and forbids Jeff from getting married to her, despite the fact that Jeff is a spider too. With no wedding and no revenge, Velma decides to go ahead and conquer Earth, just like her parents wanted.

While Billy's dad is underwear shopping, Billy wears his dad's lucky pants, and accidentally rips them with Grim's scythe. Billy opens the door to his house expecting the Powerpuff Girls but it turns out to be the Sector V operatives. Numbuh 1 disguises as Billy while Billy is taken back to the Deep Sea Lab. Mandy arrives at Billy's house and knows Numbuh 1 is not Billy, and tortures him into revealing the truth. Meanwhile, the Delightful Children from Down the Lane and Billy accidentally fuse with the scythe's power to create the Delightful Reaper. Mandy takes over the KND by fooling Numbuh 362 and the rest of the KND, but Numbuh 5 knows she is not Numbuh 1, but is taken to the med lab. The Delightful Reaper assimilates nearly all of Endsville (including Numbuh 2) and grows more powerful. Numbuh 1 and Grim try to get the KND to see the truth, but are imprisoned. Numbuh 5 escapes and finds Numbuh 1 and Grim. Grim and Numbuh 1 fuse with the Bone of Barnacles and become the Skeleton Samurai. Mandy, in her M.A.N.D.R.O.B.O.T. (Monkeys And Nice Doggies Ride On Bodies Of Turtles), fights the Delightful Reaper, and so does the Skeleton Samurai, but they cannot defeat it. Grim finds out that the pants belong to Billy's dad (which are shown to be immune to lasers, supernatural energies and mustard). Mandy is their only hope to defeat the Reaper, but instead she fuses with the Reaper. Billy's dad takes off the pants, and the Samurai Skeleton destroys the Reaper, freeing all of the assimilated children inside it. Mandy becomes furious with Numbuh 1 and Grim, and escapes to vow revenge. Numbuh 1 is mistaken to be Billy by Billy's dad, who punishes him for ruining his lucky pants, as Billy, on the other hand, disguises as Numbuh 1, causing the KND to throw various objects at him in response to prevent what happened that day.Note: This is an episode of Codename: Kids Next Door.

Billy looks into Grim's trunk and sees a monster and names it Myron. But when Billy brings Myron outside to his backyard, he gets eaten.

B2

"Macaroni Man"

October 24, 2006 (2006-10-24)

Billy's Dad has forgotten to buy Billy's present for his birthday again, and every time Billy's Dad buys a present for Billy, he will get distracted by a "Rocket" Kiddie Ride. This time, however, he found a way to give Billy a present that will be "The greatest gift ever, made by the hands of Man." It turns out, however, that Billy's Dad gave Billy a macaroni bike, and that the macaroni Billy's Dad used are the ones supposed to be used for the macaroni salad. The short ends with everyone eating macaroni salad while Grim vomits upon learning the truth of the secret of the macaroni salad (Motor Oil).

B3

"Cake It to the Limit"

October 25, 2006 (2006-10-25)

Grim decides to make a cake for Billy's birthday, but he and Mandy end up making a Devil's Food cake that comes alive and began wrecking the kitchen. The cake hops on Grim's face but Mandy smashes it and splatters it all over the kitchen. Grim and Mandy give Billy a cake covered kitchen, much to Billy's delight.

B4

"Makeover the Top"

October 25, 2006 (2006-10-25)

Irwin finishes wrapping Billy's present and buys a huge present for Mandy as well. He decides it is not big enough, however, so his dad decides to teach him how to dance. Irwin writes her a rap and Irwin's dad ends up teaching him how to work out instead of dancing. Irwin shows his moves to Mandy, but Mandy rejects him; Irwin also gets a wedgie from Sperg.

B5

"The Uninvited"

October 26, 2006 (2006-10-26)

Dracula was heading for the bingo hall when he ran into Pud'n who was on his way to Billy's party. Dracula was insulted he was not invited to the party and decides to crash it. Harold will not let him in and accidentally calls him old. Dracula starts dancing and breaks all of his bones, much to Harold's disgust. Harold lets him in so he will stop.

B6

"Death of the Party"

October 26, 2006 (2006-10-26)

Billy blows out the candles off his cake and Dracula turns to leave, but Billy stops him and forces him to stay for games. They play Pictionary where he draws Abraham Lincoln, but no one guesses it. Everyone turns to leave but Billy stops them and forces them to party all night. Billy decides to get a pinata, but the stores are closed so Billy forces them to stay all night until Grim and the others decide to use Billy as a piñata.